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Randy L. Jensen

✓ In this article, the author provides a brief description of the role of hypoxia in the tumorigenesis of gliomas and suggests potential ways of exploiting this role to design treatment modalities. Tumor hypoxia predicts the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiation therapy, invasive potential, and decreased patient survival for many human malignancies. Various methods of measurement of tumor hypoxia are discussed, including direct measurement and imaging methods.

The role of hypoxia-responsive molecules, especially hypoxia-inducible factor-1 (HIF-1), in glioma tumorigenesis is explored. Treatment modalities regulated by hypoxia are proposed and some potential strategies reviewed. The progression of a low-grade astrocytoma to a glioblastoma multiforme may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of cells that overexpress hypoxia-responsive molecules, such as HIF-1. In this model, intratumoral hypoxia causes genetic changes that produce a microenvironment that selects for cells of a more aggressive phenotype.

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Randy L. Jensen


The term “cauda equina syndrome” (CES) has been used to describe the signs and symptoms in patients with compressive neuropathy of multiple lumbar and sacral roots. This syndrome is well known as an indication for surgical intervention in treating lumbar spine disease, but relatively unknown as a postoperative complication following surgery for disease. In this study the author describes two cases of CES that occurred following uneventful lumbar spine procedures—one microdiscectomy and one decompressive laminectomy.


Preoperative, operative, and postoperative management is discussed and the relevant literature reviewed. One patient suffered perineal numbness and bowel and bladder difficulty following a decompressive laminectomy. Postoperative imaging studies were negative for residual lesion and the treatment goal pursued was partial long-term resolution of symptoms. The second patient had progressive numbness and weakness in the lower extremities. Results of urgent postoperative magnetic resonance imaging studies were inconclusive and repeated exploration was performed within hours of the initial procedure. The patient made a full recovery, although the intraoperative findings did not reveal a clear cause of the patient's symptoms.


Postoperative symptoms of partial or complete CES represent a medical emergency, especially if they are progressive. It is necessary to perform urgent postoperative imaging in patients, but the results are not always helpful. Surgical exploration is warranted if a mass lesion is demonstrated on imaging studies or if symptoms progress and the disease origin is not clear based on available information.

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Matthew Womeldorff, David Gillespie and Randy L. Jensen

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Brian T. Ragel and Randy L. Jensen

In this article the authors provide a brief description of the current understanding of meningioma genetics. Chromosome 22 abnormalities, especially in the Neurofibromatosis Type 2 (NF2) gene, have been associated with meningioma development. Loss of heterozygosity of chromosome 22 occurs in approximately 60% of meningiomas; however, loss of NF2 gene function occurs in only one third of these lesions. This discrepancy supports the theory that a second tumor suppressor gene exists on chromosome 22, and the authors introduce several possible gene candidates, including BAM22, LARGE, INI1, and MN1 genes. Deletions of 1p have also been shown to correlate with meningioma progression. The genetic similarities and differences among sporadic, NF2-associated, pediatric, and radiation-induced meningiomas are discussed, with the observation that the nonsporadic meningiomas have a higher incidence of multiple chromosomal abnormalities at presentation. Ultimately, a better understanding of the molecular pathways of meningioma tumorigenesis will lead to new, successful treatments.

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Randy L. Jensen, Scott Soleau, Mihir K. Bhayani and Dustin Christiansen

Object. Vascular endothelial growth factor (VEGF) has been implicated in meningioma tumorigenesis and growth. The production of VEGF is regulated by hypoxia inducible factor—1α (HIF-1α), especially under conditions of hypoxia. In this study, the authors examine the expression of HIF-1α and VEGF in meningiomas, with a special emphasis on conditions of hypoxia, such as preoperative embolization, and on in vitro studies in cultured cells.

Methods. Meningiomas obtained in 142 patients were studied using immunohistochemical methods to detect HIF-1α and the results were correlated with the extent or lack of preoperative embolization and expression of VEGF. Primary meningioma cell cultures were established and cell culture experiments were performed using a hypoxia chamber to stimulate HIF-1α and VEGF production. Expression of HIF-1α in primary meningioma cell cultures was measured using immunoblot assays. The VEGF secretion was measured using enzyme-linked immunosorbent assay.

Half of the meningiomas studied were positive for HIF-1α, with a strong correlation between complete embolization and HIF-1α expression. Most of the meningiomas studied expressed VEGF protein, and VEGF expression did not correlate with the degree of embolization. A strong correlation was found between VEGF and HIF-1α expression in immunohistochemical studies. Secretion of VEGF is increased by hypoxia and growth factor stimulation. In meningiomas, growth factors stimulate HIF-1α expression. The role of hypoxia is less clear.

Conclusions. The expression of HIF-1α is increased by complete preoperative embolization of meningiomas. The expression of HIF-1α also correlates with VEGF secretion in meningiomas. Growth factor and hypoxic stimulation both contribute to VEGF control, but which is most important (or whether both are equally important) will require further studies.

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W. Scott Jellish, Randy L. Jensen, Douglas E. Anderson and John F. Shea

Object. Recurrent laryngeal nerve (RLN) injury occurs after anterior cervical spine procedures. In this study the authors used intraoperative electromyographic (EMG) monitoring of the posterior pharynx as a surrogate for RLN function and monitored endotracheal tube (ET) cuff pressure to determine if there was an association between these variables and clinical outcome.

Methods. Sixty patients in whom anterior cervical spine procedures were to be performed comprised the study population. After intubation, the ET cuff was adjusted to a just-seal volume and attached to a pressure monitor. A laryngeal surface electrode was placed in the posterior pharynx, and spontaneous EMG activity was monitored throughout the procedure. Cuff pressures and EMG activity were recorded during neck retraction and when EMG activity increased 20% above baseline. Patients were divided into two groups: those with sore throat/dysphonia and those without symptoms. Cuff pressures and EMG values were compared between groups, and the differences were correlated with clinical outcome.

Conclusions. Hoarseness immediately after surgery was reported in 38% of patients whereas 15% exhibited severe symptoms. In symptomatic patients the period of intubation had been longer, and the ET cuff pressures had been elevated. In most patients EMG activity increased during insertion of the retractor and decreased after its removal. In these patients a greater number of episodes of elevated EMG activity during surgery were also noted. Two patients experienced prolonged hoarseness, and one required teflon injections of the vocal fold. This patient's EMG activity increased (15–18 times baseline) during surgery. In the few patients who were symptomatic with increased EMG activity, neither the timing nor direction of change could be associated with symptoms. Intubation time and elevated ET cuff pressure were the most important contributors to dysphonia and sore throat after anterior cervical spine surgery.

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Dennis C. Shrieve, Lisa Hazard, Kenneth Boucher and Randy L. Jensen

Object. Benign meningiomas have been shown to be equally well controlled with single-dose radiosurgery (15 Gy) and fractionated doses of 54 Gy in 30 fractions after adequate follow up. For a subset of patients with meningioma, the optic apparatus is dose limiting when considering single-dose stereotactic radiosurgery, with tolerance estimated to be 8 to 10 Gy. Recently, hypofractionated regimens have been used to treat benign meningiomas with a small number of fractions. An analysis of the expected efficacy of hypofractionation compared with the estimated optic tolerance to fractionated radiotherapy was undertaken.

Methods. Using the assumption that 15 Gy in one fraction and 54 Gy in 30 fractions are isoeffective for control of benign meningioma, an α/β for meningioma is calculated to be 3.28 Gy. Invoking a 10% error for these doses (15 Gy ± 10% is equivalent to 54 Gy ± 10%) results in upper and lower limits of the estimate for α/β of 3.85 Gy and 2.7 Gy. Using these estimates, isoeffect curves for control of meningioma were constructed for fraction numbers of one to 45. Best estimates of optic nerve/chiasm tolerance to single doses of radiation are 8 to 10 Gy, with the reported incidence of optic neuropathy increasing significantly at higher doses. This is consistent with the optic ret model, which also predicts for optic tolerance following fractionated radiotherapy. Comparison of optic tolerance and estimates of efficacious doses at fraction numbers between one and 30 were made. Statistical estimates of patient numbers and duration of follow up required to rule out optic neuropathy following radiotherapy were made. Single doses of radiation required to treat benign meningioma optimally (13.5–16.5 Gy) clearly exceed the estimated and reported clinical tolerance of the optic nerves and chiasm. The application of equivalent biological doses in a small number of fractions continues to exceed optic tolerance until at least 25 fractions are applied.

Conclusions. The use of small numbers of fractions to treat patients with meningioma when portions of optic nerve or chiasm receive full dose may result in undertreatment of the tumor and/or exceeding optic nerve tolerance. In such cases standard fractionation is recommended. Ruling out a low, yet unacceptable, risk of optic neuropathy may require the close study of many patients with long-term follow-up evaluation.

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Brian T. Ragel, Randy L. Jensen and William T. Couldwell

✓In this article the authors discuss the rationale and research supporting the hypothesis that meningioma tumorigenesis may, in part, be driven by overexpression of cyclooxygenase-2 (Cox-2) and that treatment with celecoxib, a selective Cox-2 inhibitor, may hold therapeutic promise. Because therapies for recurrent or aggressive meningiomas (atypical or malignant subtypes) such as chemotherapy and radiotherapy generally offer little therapeutic benefit, interest in targeting Cox-2 has grown. This rate-limiting enzyme of prostaglandin synthesis can be inhibited with nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and celecoxib. Treatment with NSAIDs has been shown to curb the tumorigenic properties of prostaglandins in several cancer models via both Cox-2-dependent and -independent mechanisms. In addition, celecoxib is well tolerated in humans, making its use as a chronic therapy for meningiomas attractive.

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Randy L. Jensen, David Gillespie, Paul House, Lester Layfield and Clough Shelton

Object. Endolymphatic sac (ELS) tumors are low-grade malignancies of the temporal bone that are associated with von Hippel—Lindau (VHL) disease but can also occur sporadically. The VHL gene product VHL protein is important in the regulation of hypoxia inducible factor (HIF)-1α, which controls expression of molecules that are important in angiogenesis and cell metabolism. In this study the authors examine the role of VHL and HIF-1 in ELS tumors.

Methods. The ELS tumors from three patients were examined using the following method: DNA from tumor tissue was isolated, amplified by polymerase chain reaction and the VHL gene sequence was compared with the known wild-type sequence. Loss of heterozygosity (LOH) studies were performed to confirm the sequencing data. Immunohistochemical evaluation for VHL, HIF-1α, vascular endothelial growth factor (VEGF), and carbonic anhydrase IX (CA IX) was performed. Snap-frozen tumor tissue was examined using Western blot and HIF-1 immunoassays for HIF-1α and VHL expression.

Two patients had sporadic ELS tumors and the other one suffered from VHL disease. Results of VHL gene sequencing were normal in the tissue derived from the sporadic ELS tumors. The ELS tumor, pheochromocytoma, and spinal hemangioblastoma were heterozygous for the same C-to-A transversion found in the germline carried by the patient with VHL disease. No LOH was detected in the tumor tissue obtained in the patient with VHL disease. Expression of HIF-1α, VEGF, and CA IX evaluated using immunohistochemical studies was elevated in the VHL-associated tumors. Nevertheless, Western blots and immunoassays for HIF-1α did not show elevated expression in these tumors.

Conclusions. The sporadic and VHL disease—associated ELS tumors in this study had normal VHL-mediated HIF-1 regulation. This is a result of normal VHL gene expression in the case of the sporadic ELS tumor. In the VHL-associated ELS tumor, this is due to one normal copy of the VHL gene and adequate VHL gene expression.

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Ricky Chen, Vijay M. Ravindra, Adam L. Cohen, Randy L. Jensen, Karen L. Salzman, Andrew P. Prescot and Howard Colman

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.